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E-grāmata: Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications

Edited by (Milestone Development Services), Edited by (Bristol-Myers Squibb Pharmaceutical Research Institute)
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"This book examines the background, industrial context, process, analytical methodology, and technology of metabolite identification. It emphasizes the applications of metabolite identification in drug research. While primarily a textbook, the book also functions as a comprehensive reference to those in the industry. The authors have worked closely together and combine complementary backgrounds to bring technical and cultural awareness to this very important endeavor while serving to address needs withinacademia and industry It also contains a variety of problem sets following specific sections in the text"--Provided by publisher.

This book examines the background, industrial context, process, analytical methodology, and technology of metabolite identification. It emphasizes the applications of metabolite identification in drug research. While primarily a textbook, the book also functions as a comprehensive reference to those in the industry. The authors have worked closely together and combine complementary backgrounds to bring technical and cultural awareness to this very important endeavor while serving to address needs within academia and industry It also contains a variety of problem sets following specific sections in the text.

Recenzijas

"It is a state-of-the-art and mostly comprehensive overview of the field. It will be a valuable source of information for all those who want to start in the fields of drug metabolism and MS, e.g., PhD students, but also senior scientists, etc."  (Analytical and Bioanalytical Chemistry, 31 July 2012)

"Overall, Mass Spectrometry in Drug Metabolism and Pharmacokinetics is a valuable and interesting resource for a broad readership, including scientists starting to work in DMPK as well as undergraduate and graduate students getting involved in drug discovery and characterization by means of MS." (J Am Soc Mass Spectrom, 2011) "Placing the imaging technology in the context of the principles and applications of drug design, the book can serve as a textbook for either field." (Book New, 1 August 2011)

 

Foreword ix
Tom Baillie
Preface xi
Mike Lee
Mingshe Zhu
Contributors xv
PART I BASIC CONCEPTS OF DRUG METABOLISM AND DISPOSITION
1(254)
1 Progression of Drug Metabolism
3(10)
Ronald E. White
1.1 Introduction
1.2 Historical Phases of Drug Metabolism
1.2.1 The "Chemistry" Phase (1950-1980)
1.2.2 The "Biochemistry" Phase (1975---Present)
1.2.3 The "Genetics" Phase (1990---Present)
1.2.4 The "Biology" Phase (2010 and Beyond)
1.3 Next Step in the Progression of DM
1.3.1 New Regulatory Expectation
1.3.2 New Challenges for Technology
1.4 Perspective on the Magnitude of the Challenge
1.4.1 Ultimate Limits on Metabolite Quantitation
1.4.2 Practical Limits on Metabolite Quantitation
1.4.3 Natural Limit Due to Dose Size
1.5 Are There More Sensitive Alternatives to MS?
1.6 Summary
References
2 Common Biotransformation Reactions
13(30)
Bo Wen
Sidney D. Nelson
2.1 Introduction
2.2 Oxidative Reactions
2.2.1 Cytochrome P450 Oxidative Reactions
2.2.2 Oxidations by Flavin Monooxygenases
2.2.3 Oxidations by Monoamine Oxidases
2.2.4 Oxidations by Molybdenum Hydroxylases
2.2.5 Oxidations by Alcohol and Aldehyde Dehydrogenases
2.2.6 Oxidations by Peroxidases
2.3 Reductive Reactions
2.3.1 Reductions by Cytochrome P450s
2.3.2 Reductions by Molybdenum-Containing Enzymes
2.3.3 Reductions by Alcohol Dehydrogenases and Carbonyl Reductases
2.3.4 Reductions by Cytochrome P450 Reductase and Quinone Oxidoreductase
2.3.5 Reductions by Intestinal Microflora
2.4 Hydrolytic Reactions
2.4.1 Hydrolysis by Epoxide Hydrolases
2.4.2 Hydrolysis of Esters, Amides, and Related Structures
2.5 Glucuronidation Reactions
2.5.1 Glucuronidation of Hydroxy Groups
2.5.2 Glucuronidation of Amines and Amides
2.5.3 Glucuronidation of Thiols and Thiocarbonyl Compounds
2.5.4 Glucuronidation of Relatively Acidic Carbon Atoms
2.6 Sulfation Reactions
2.6.1 Sulfation of Alcohols
2.6.2 Sulfation of Hydroxylamines and Hydroxyamides
2.6.3 Sulfation of Amines and Amides
2.7 Acylation Reactions
2.7.1 Acetylation of Primary Amines and Hydrazines
2.7.2 Amino Acid Conjugation of Carboxylic Acids
2.7.3 Chemical Acylations
2.8 Methylation Reactions
2.8.1 Methylation of Catechols
2.8.2 Methylation of Thiols
2.8.3 Methylation of Amines
2.9 Glutathione Conjugation Reactions
2.9.1 GSH Conjugation of Epoxides
2.9.2 GSH Conjugation of Conjugated Enone/Enal and Similar Systems
2.9.3 GSH Conjugations at Saturated and Unsaturated Carbon Atoms
2.9.4 GSH Conjugation at Heteroatoms
2.10 Conclusions
References
3 Metabolic Activation of Organic Functional Groups Utilized in Medicinal Chemistry
43(40)
Amit S. Kalgutkar
3.1 Introduction
3.2 Bioactivation of Drugs
3.3 Experimental Strategies to Detect Reactive Metabolites
3.4 Functional Group Metabolism to Reactive Intermediates
3.4.1 Two-Electron Oxidations on Electron-Rich Aromatic Ring Systems
3.4.2 N-Hydroxylation of Anilines
3.4.3 Hydrazines
3.4.4 Bioactivation of Reduced Thiols
3.4.5 Epoxidation of sp2 and sp Centers
3.4.6 Thiazolidinedione Ring Bioactivation
3.4.7 α, β-Unsaturated Carbonyl Compounds
3.4.8 Haloalkanes
3.4.9 Carboxylic Acids
3.5 Structural Alerts and Drug Design
3.6 Reactive Metabolite Trapping and Covalent Binding Studies as Predictors of Idiosyncratic Drug Toxicity
3.7 Dose as an Important Mitigating Factor for IADRs
3.8 Concluding Remarks
References
4 Drug-Metabolizing Enzymes, Transporters, and Drug---Drug Interactions
83(68)
Steven W. Louie
Magang Shou
4.1 Introduction
4.2 Drug-Metabolizing Enzymes
4.2.1 CYPs
4.2.2 UDP---Glucuronosyl transferases
4.2.3 Sulfotransferases
4.2.4 Glutathione-S-Transferases
4.2.5 Regulation of Human CYPs
4.3 Metabolism-Based DDIs
4.3.1 Reaction Phenotyping
4.3.2 Reversible CYP Inhibition
4.3.3 Time-Dependent Inhibition
4.3.4 Prediction of Clinical DDIs from CYP Induction
4.3.5 Factors Affecting DDI Prediction
4.4 CYP Conclusion
4.5 Drug Transporters
4.5.1 Key ADME Transporters
4.6 Tools of the Transporter Trade
4.6.1 Absorption and Permeability
4.6.2 Caco-2 Permeability
4.6.3 PAMPA
4.6.4 Immobilized Artificial Membrane
4.7 Uptake and Efflux Transporter Tools
4.7.1 Transfected Cell Lines
4.7.2 Uptake Assays
4.7.3 Transwell Efflux Assays
4.7.4 Membrane Vesicles
4.7.5 Hepatocyte Sandwich Cultures
4.7.6 Transgenic Mice
4.8 Sample Analysis
4.9 Automation
4.9.1 Cell Maintenance Systems
4.9.2 Robotic Liquid-Handling Systems
4.10 In Vitro DDI Assays
4.11 In Vitro---In Vivo Correlations
4.12 Kinetic Models
4.13 Transporter Conclusion
Acknowledgment
References
5 Experimental Models of Drug Metabolism and Disposition
151(46)
Gang Luo
Chuang Lu
Xinxin Ding
Donglu Zhang
5.1 Introduction
5.2 ADME Study Strategy in Drug Discovery
5.2.1 Step-by-Step Strategy
5.2.2 Issue-Driven Strategy
5.2.3 PK---PD and PK---TK Considerations
5.3 ADME Experimental Models
5.3.1 In Vitro Models
5.3.2 In Situ and Ex Vivo Models
5.3.3 In Vivo Models
5.3.4 Engineered Mouse Models
5.3.5 In Silico Modeling
5.4 Data Interpretation
5.4.1 Species Difference
5.4.2 In vitro---In Vivo Discrepancy
5.4.3 Enzyme---Transporter Interplay
5.4.4 Interindividual Differences
5.4.5 Drug---Drug Interaction
5.4.6 Multiple Other Factors Affecting Metabolic Pathways
5.5 Summary
Acknowledgments
References
6 Principles of Pharmacokinetics: Predicting Human Pharmacokinetics in Drug Discovery
197(32)
Takehito Yamamoto
Akihiro Hisaka
Hiroshi Suzuki
6.1 Introduction
6.1.1 General Introduction
6.1.2 Relationship between Drug Efficacy and Concentration
6.1.3 Prediction of Pharmacokinetics by Extrapolation from Animal Data
6.2 Physiological Pharmacokinetics
6.2.1 Why Is a Physiological Pharmacokinetic Model Necessary?
6.2.2 Clearance
6.2.3 Volume of Distribution
6.2.4 Relationship between Intrinsic Clearance and Organ Clearance
6.2.5 Estimation of Permeability-Limited Clearance
6.3 Prediction of Absorption
6.3.1 Determinants of Bioavailability
6.3.2 Absorption Ratio
6.3.3 Dosing Vehicle and Feeding State
6.3.4 Evaluation Methods for Absorption
6.3.5 Intestinal Availability
6.4 Distribution
6.4.1 Plasma Protein Binding
6.4.2 Relationship between Drug Efficacy and Protein Binding
6.5 Metabolism and excretion
6.5.1 Estimation of Clearance
6.5.2 Estimation of Hepatic Intrinsic Clearance
6.5.3 Determination of Hepatic Intrinsic Metabolic Clearance from in vitro Experimental Data
6.5.4 Estimation of Renal Clearance
6.6 Drug---Drug interactions
6.6.1 Importance of Determining the Contribution Ratio for Prediction of Drug---Drug Interactions
6.6.2 Methods for Determination of the Contribution Ratio
6.7 Practical issues That Need to Be Considered
6.7.1 Evaluation of PK During the Exploratory Stage
6.7.2 Evaluation of PK During the Development Stage
Abbrevations and Notations
References
7 Drug Metabolism Research as Integral Part of Drug Discovery and Development Processes
229(26)
W. Griffith Humphreys
7.1 Introduction
7.2 Metabolic Clearance
7.2.1 General
7.2.2 Prediction of Human Clearance
7.2.3 In vivo Methods to Study Metabolism
7.2.4 Screening Strategies
7.3 Metabolite Profiling/Mass Balance Studies
7.4 Safety Testing of Drug Metabolites
7.5 Reaction Phenotyping
7.6 Assessment of Potential Toxicology of Metabolites
7.6.1 Reactive Metabolite Studies---General Considerations
7.6.2 Reactive Metabolite Studies---In Vitro
7.6.3 Reactive Metabolite Studies---In Vivo
7.6.4 Metabolite Contribution to Off-Target Toxicities
7.7 Assessment of Potential for Active Metabolites
7.7.1 Detection of Active Metabolites During Drug Discovery
7.8 Summary
References
PART II MASS SPECTROMETRY IN DRUG METABOLISM: PRINCIPLES AND COMMON PRACTICE
255(128)
8 Theory and Instrumentation of Mass Spectrometry
257(34)
Gerard Hopfgartner
8.1 Basic Concepts and Theory of Mass Spectrometry
8.1.1 Historical Perspective
8.1.2 Isotopes
8.2 Major Components of a Mass Spectrometer
8.3 Ion Sources
8.3.1 Electron Impact Ionization
8.3.2 Electrospray Ionization
8.3.3 Chemical Ionization and Atmospheric Pressure Chemical Ionization
8.3.4 Atmospheric Pressure Photoionization
8.3.5 Matrix-Assisted Laser Desorption Ionization
8.3.6 Other Ionization Techniques
8.4 Mass Analyzers
8.4.1 Triple Quadrupole
8.4.2 Ion Trap and Linear Ion Trap
8.4.3 Time-of-Flight Spectrometry
8.4.4 Fourier Transform Mass Spectrometry
References
9 Common Liquid Chromatography---Mass Spectrometry (LC---MS) Methodology for Metabolite Identification
291(30)
Lin Xu
Lewis J. Klunk
Chandra Prakash
9.1 Introduction
9.2 Strategies for Metabolite Identification
9.2.1 Detection of Metabolites
9.2.2 Structure Elucidation of Metabolites
9.3 In Silico Tools
9.4 Conclusions and Future Trends
9.5 Acknowledgment
References
10 Mass Spectral Interpretation
321(32)
Li-Kang Zhang
Birendra N. Pramanik
10.1 Molecular Weight and Empirical Formula Determination
10.1.1 Formation of Adduct Ions
10.1.2 Isotopic Clusters
10.1.3 Nitrogen Rule
10.1.4 Accurate Mass Measurement
10.1.5 Double-Bond Equivalency (DBE)
10.2 Common Fragmentation Reactions
10.3 Practical Applications
10.3.1 Metabolite Profiling by LC---MS
10.3.2 Special Strategies for Characterization of Drug Metabolites by LC---MS
10.4 Conclusion
Acknowledgment
References
11 Techniques to Facilitate the Performance of Mass Spectrometry: Sample Preparation, Liquid Chromatography, and Non-Mass-Spectrometric Detection
353(30)
Mark Hayward
Maria D. Bacolod
Qing Ping Han
Manuel Cajina
Zack Zou
11.1 Introduction
11.2 Sample Preparation for Bioanalysis
11.2.1 Protein Precipitation
11.2.2 Solid-Phase Extraction
11.2.3 Turbulent Flow Chromatography
11.2.4 Liquid---Liquid Extraction
11.2.5 Plasma and Blood Sample Preparation
11.3 Sample Preparation for Metabolite Profiling and Identification
11.3.1 In Vitro Sample Preparation
11.3.2 Plasma, Urine, and Bile Sample Preparation
11.3.3 Fecal and Tissue Sample Preparation
11.4 Liquid Chromatographic Separation in Bioanalysis
11.4.1 Basic Approach and Method Development
11.4.2 Splitting LC Flow for Introduction into MS
11.4.3 Stepping up Productivity with Fast LC Separations
11.4.4 Using SFC and MS for Chiral Bioanalysis
11.5 Liquid Chromatographic Separation Technologies in Metabolite Profiling
11.5.1 LC Methods for Metabolite Profiling of Nonradiolabeled Compounds
11.5.2 LC Methods for Metabolite Profiling of Radiolabeled Compounds
11.6 Liquid Chromatographic Detection
11.6.1 UV Absorbance Detection
11.6.2 Radioactivity Detection
11.6.3 Nuclear Magnetic Resoance
References
PART III APPLICATIONS OF NEW LC---MS TECHNIQUES IN DRUG METABOLISM, DISPOSITION
383(184)
12 Quantitative In Vitro ADME Assays Using LC---MS as a Part of Early Drug Metabolism Screening
385(22)
Walter Korfmacher
12.1 Introduction
12.2 Metabolic Stability Assays
12.3 Drug Absorption and Permeability Assays
12.4 Cytochrome P450 (CYP) Assays
12.5 New Technology for High-Throughput Assays
12.6 Conclusions
References
13 High-Resolution Mass Spectrometry and Drug Metabolite Identification
407(42)
Russell J. Mortishire-Smith
Haiying Zhang
Kevin P. Bateman
13.1 Introduction
13.2 Challenges Presented by Different Samples
13.3 Fundamental Advantage of High-Resolution Mass Spectrometry: Specificity/Selectivity in a Single Generic Method
13.4 High-Resolution Mass Spectrometry: Important Concepts
13.5 High-Resolution Instrumentation
13.6 Advantages of High-Resolution MS: The Concept of Mass Defect Filtration
13.7 Postprocessing Strategies for Identifying Metabolites in Complex High-Resolution Data Sets
13.7.1 Classical Metabolites
13.7.2 Identifying All Other Analyte-Specific Peaks
13.8 Control Comparison
13.9 Background Subtraction
13.10 Isotope Filtration
13.11 "All-in-One" Data Analysis
13.12 Rationalization of Novel Metabolites
13.13 Assigning Product Ion Spectra Using the Power of Accurate Mass
13.14 Localization: The Final Frontier
13.15 Quantitative and Qualitative In Vivo Pharmacokinetic Data from a Single Injection per Sample
13.16 Future Opportunities
References
14 Distribution Studies of Drugs and Metabolites in Tissue by Mass Spectrometric Imaging
449(34)
Richard F. Reich
Daniel P. Magparangalan
Timothy J. Garrett
Richard A. Yost
14.1 Introduction
14.2 Tissue Imaging Techniques
14.3 Mass Spectrometric Imaging Background
14.4 MSI Methodology
14.4.1 Mass Analyzers
14.4.2 Ionization Sources
14.4.3 Tissue Preparation
14.4.4 MALDI Matrix
14.4.5 Quantitative MALDI---MS
14.5 Applications of MSI for Detection of Drug Metabolites in Tissue
14.5.1 Localizing Drugs and Their Metabolites to Verify Targeted Drug Distribution
14.5.2 Analysis of Whole-Body Tissue Sections Utilizing Mass Spectral Imaging
14.5.3 Increasing Analyte Specificity for Mass Spectral Images
14.5.4 Alternative Source Options for Mass Spectral Imaging
14.6 Conclusions
Acknowledgments
References
15 Use of Triple Quadrupole---Linear Ion Trap Mass Spectrometry as a Single LC---MS Platform in Drug Metabolism and Pharmacokinetics Studies
483(42)
Wenying Jian
Ming Yao
Bo Wen
Elliott B. Jones
Mingshe Zhu
15.1 Introduction
15.2 Instrumentation and Scan Functions
15.2.1 Instrumentation
15.2.2 Scan Functions
15.3 In vitro and In Vivo Metabolite Profiling and Identification
15.3.1 Metabolic Stability Analysis
15.3.2 Metabolic Soft Spot Determination
15.3.3 In vitro Species Comparison
15.3.4 Identification of In Vivo Oxidative Metabolites
15.4 Reactive Metabolite Screening and Characterization
15.4.1 In Vitro Reactive Metabolite Screening
15.4.2 Analysis of Adducts of Reactive Metabolites In Vivo
15.5 In vitro Drug Interaction Studies
15.5.1 Enzyme Kinetics Analysis
15.5.2 Metabolizing Enzyme Reaction Phenotyping
15.5.3 CYP Inhibition Assays
15.6 Quantification and Screening of Drugs and Small Molecules
15.6.1 PK and TK Sample Analysis
15.6.2 Tissue Imaging of Drugs
15.6.3 Screening of Drugs and Toxic Chemicals in Biological Samples
15.6.4 Analysis of Pharmaceuticals in Wastewater
15.7 Summary
References
16 Quantitative Drug Metabolism with Accelerator Mass Spectrometry
525(42)
John S. Vogel
Peter Lohstroh
Brad Keck
Stephen R. Dueker
16.1 Relevance of AMS to Drug Metabolism
16.2 Introduction to AMS
16.3 Fundamentals of AMS Instruments
16.4 Sample Definition and Interfaces
16.5 AMS Quantitation
16.6 LC---AMS Analysis of Drug Metabolites
16.7 Comparative Resolution of Fraction LC Measurements
16.8 Quantitative Extraction and Recovery
16.9 LC---AMS Background and Sensitivity
16.10 Clinical Aspects of AMS Metabolite Studies
16.11 AMS Analysis of Reactive Metabolites
16.12 Species Metabolite Comparison
16.13 New Metabolic Studies Enabled by AMS
16.14 Conclusions
References
17 Standard-Free Estimation of Metabolite Levels Using Nanospray Mass Spectrometry: Current Statutes and Future Directions
567(12)
Jing-Tao Wu
17.1 Introduction
17.2 Current Approaches for Metabolite Quantitation in the Absence of Synthetic Standards
17.3 Use of Nanospray for Standard-Free Metabolite Quantitation
17.3.1 Nanospray and Equimolar Response
17.3.2 Application of Nanospray in Estimating Metabolite Levels
17.4 Future Directions
References
18 Profiling and Characterization of Herbal Medicine and Its Metabolites Using LC---MS
579(34)
Zeper Abliz
Ruiping Zhang
Ping Geng
Dongmei Dai
Jiuming He
Jian Liu
18.1 Introduction
18.2 Characterization of Chemical Constituents in Chinese Herbal Medicine
18.2.1 Systematic Identification Method for Flavonols
18.2.2 Online Structural Characterization of Constituents in AB-8-2
18.3 Profiling the Integral Metabolism of Herbal Medicine
18.3.1 Analysis of Parent Constituents and Metabolites in Rat Bile
18.3.2 Integral Metabolic Characteristics of Flavonols in AB-8-2
18.3.3 Analysis of the Metabolites of AB-8-2 in Rat Urine
18.4 Conclusions
Acknowledgment
References
19 Liquid Chromatography Mass Spectrometry Bioanalysis of Protein Therapeutics and Biomarkers in Biological Matrices
613(32)
Fumin Li
Qin C. Ji
19.1 General Introduction
19.2 Protein Quantitation by LC---MS/MS
19.3 Protein Quantitation Using Intact Proteins by LC---MS/MS
19.4 Protein Quantitation Using Representative Peptides by LC---MS/MS
19.5 Consideration of Internal Standard for Protein Quantitation
19.6 Matrix Effect, Matrix Suppression/Enhancement, and Recovery
19.7 Sensitivity Enhancement via Immunocapture/Purification
19.8 Sensitivity Enhancement via Depletion of Abundant Proteins
19.9 Practical Aspects of LC---MS Assay for Proteins in Drug Development
19.9.1 "Fit-for-Purpose" Assay Development Strategy
19.9.2 LC---MS/MS Assay for Pegylated Proteins, Protein Homologs, and Posttranslational Modified Proteins
19.9.3 Total and Free Protein Concentration Measurement
19.9.4 Protein Metabolism
19.10 Conclusions
Acknowledgments
References
20 Mass Spectrometry in the Analysis of DNA, Protein, Peptide, and Lipid Biomarkers of Oxidative Stress
645(40)
Stacy L. Gelhaus
Ian A. Blair
20.1 Introduction
20.2 DNA Biomarkers of Oxidative Stress
20.2.1 Background
20.2.2 Oxidative Damage to DNA Bases: 8-Oxo-dGuo
20.2.3 Oxidative Damage to DNA Bases: Formamidopyrimidines
20.2.4 Lipid-Hydroperoxide-Derived Genotoxins
20.2.5 Lipid-Hydroperoxide-Derived DNA Adducts
20.2.6 DNA Adducts from Other Aldehydes and Base Propenals
20.3 Protein and Peptide Biomarkers of Oxidative Stress
20.3.1 Introduction
20.3.2 Protein Adducts from Lipid-Hydroperoxide-Derived Bifunctional Electrophiles
20.3.3 Oxidized Methionine, Histidine, and Tyrosine
20.3.4 Lipid Hydroperoxide-Derived GSH Adducts
20.4 Lipid Biomarkers of Oxidative Stress
20.4.1 Introduction
20.4.2 Isoprostanes
20.4.3 Hydroxyeicosatetraenoic Acids (HETEs)
20.5 Creatinine: The Common Denominator
20.6 Summary and Conclusions
Acknowledgments
References
21 LC---MS in Endogenous Metabolite Profiling and Small-Molecule Biomarker Discovery
685(38)
Michael D. Reily
Petia Shipkova
Serhiy Hnatyshyn
21.1 Introduction
21.2 Measuring the Metabolome
21.3 Analytical Approaches
21.3.1 Fingerprinting Methods
21.3.2 Nontargeted Metabonomics
21.3.3 Targeted Metabonomics
21.4 Experimental Design
21.4.1 Sample Selection
21.4.2 Sample Preparation
21.4.3 Chromatography and Mass Spectral Detection
21.4.4 Quality Controls
21.5 Data Processing and Analysis
21.5.1 Anatomy of an LC---MS Profile
21.5.2 Processing
21.5.3 Data Analysis
21.6 Conclusion
References
Appendix 723(4)
Index 727
MIKE S. LEE, PhD, is President of Milestone Development Services. His recent work has involved the development of automated orthogonal control systems for electrospray ionization. Formerly, Dr. Lee was director of analytical research and development at Bristol-Myers Squibb (BMS) Pharmaceutical Research Institute where he led interdisciplinary teams that contributed to the Food and Drug Administration's approval of Buspar® and Serzone®, and the accelerated development and approval of Taxol®. In addition, he has authored over forty scientific papers and issued patents. MINGSHE ZHU, PhD, is a drug metabolism researcher at Bristol-Myers Squibb, where he leads a team that investigates biotransformation in new drug discovery and preclinical drug metabolism and pharmacokinetics in development. His teams have provided key metabolism and disposition information for regulatory approval of Abilify® and NDA submission of Dapagliflozin. Dr. Zhu's research interests include LC/MS technology, optimization of ADME properties, metabolic activation, and regulatory drug metabolism. He has been frequently invited to speak and teach short courses at conferences/workshops and has coauthored over sixty research articles and one book.
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